A common technical problem associated with many drugs is their poor water solubility. Approximately 40% of potentially new drugs identified by pharmaceutical companies are poorly soluble in water, greatly hindering their further development. Furthermore, for specific application areas such as administration of drugs via drinking water, the poor water solubility of drugs is a major obstacle. In addition, low water solubility greatly limits the bioavailability and absorption of these agents. Therefore, technologies aimed at improving the dissolution profile of drugs are continuously being developed.
Recently, various nanonization strategies have emerged to increase the dissolution rate and bioavailability of numerous drugs that are poorly soluble in water and during the past decade, several drug nanoformulations have been clinically approved or are under clinical investigation (see review of Chen et al., 2011 below). Major research efforts have been focused on the development of enabling nanoformulation technologies to improve product properties, while keeping production costs as low as possible. Important parameters for providing a suitable nanoformulation include:                minimizing the particle size, in order to obtain the highest possible solubility and dissolution rate.        improving the stability of the particles, in particular for the manufacturing of a nanosuspension        keeping production costs as low as possible        improving the bioavailability, . . . .        
Nanoformulations exist in various forms such as for example nanocrystals, nanoemulsions, and polymeric micelles. Nanocrystals are nano-sized crystals of the drug compound having dimensions generally less than 1 μm. It is common knowledge that the smaller the particle size, the higher the effective surface area, thereby resulting in an increased dissolution rate of the drug. Various methods exist for the preparation of nanocrystals such as nanoprecipitation, high-pressure homogenization and milling. The procedure making use of milling generally exists in charging a milling chamber with milling beads, dispersion media (e.g. water), drug powders and stabilizers. Subsequently, the beads are rotated at very high speed to generate strong shear forces to disintegrate drug powders into nanoparticles. Not only dry milling techniques exist, but also wet milling procedures have been developed making use of zirconium beads (Takatsuka, T. et al. (2009) Nanonizing of poorly soluble compounds using rotation/revolution mixer. Chem. Pharm. Bull. (Tokyo) 57, 1061-1067).
Exemplary nanoformulations of water-insoluble drugs that are approved for clinical use or that are still in clinical trials, prepared by milling techniques are represented in table 1.
TABLE 1Available nanoformulations prepared by millingtechniques (Chen et al., Drug Discovery Today Volume16 Issues 7-8, April 2011, pages 654-360)OtherDosageTradenameDrugingredientsFormRapamune ®SirolimusPVP, poloxamer 188Oral TabletEmend ®EprepitantHPC, SDSOral CapsuleTricor ®FenofibrateHPMC, SDS,Oral TabletCrospovidoneMegace ES ®MegestrolHPMC,Oral SuspensionDocusate SodiumInvega ®PaliperidoneTween 20, PEG 4000IntramuscularsuspensionPVP: polyvinylpyrrolidone, HPC: Hydroxypropyl cellulose, SDS: sodium dodecyl sulphate, HPMC: Hydroxypropyl methylcellulose, PEG: polyethylene glycol
Although the conventional nanonization procedures often result in increased solubility of the drug, there is a continuous need for further improvements to obtain better solubility rates for poorly soluble drugs. As evident from table 1, various additional ingredients have been added to the currently developed nanoformulations in order to obtain the best possible formulations. All of these compositions comprise at least one (co)polymer such as PVP, HPC, HPMC, PEG 4000 and Poloxamer; and most of them further comprises a surfactant such as SDS, Docusate and Tween 20. Also US20080213383 provides pharmaceutical nanoparticles comprising (co)polymers such as HPMC acetate succinate and HPMC phthalate.
We have now surprisingly found that a wet milling process not making use of (co)polymers but dicarboxylic acids and a surfactant instead results in a stable suspension of drugs comprising cocrystals having a particle size in the nanometer range.
WO2004078163 provides a co-crystal composition comprising an API and a co-crystal former, wherein the API and co-crystal former are hydrogen bonded to each other. Furthermore, although this patent application provides exhausting lists of API's and co-crystal formers, none of the few exemplified formulations were prepared by a nanonization method. Therefore a person skilled in the art, taken the teaching of this patent application, does not have indications that any of the disclosed co-crystal formers, let it be which one of them, could be used for optimizing a nanonization procedure.
WO2011036676 provides pharmaceutical cocrystals of temozolomide with co-crystal formers selected from aliphatic and aromatic carboxylic acids, including dicarboxylic acids. However, again no nanoparticle formulations are provided, and as such no teaching with regard to the use of co-crystal formers for optimizing a nanonization procedure are contained therein.
Cocrystal formation of drugs making use of dicarboxylic acids has been investigated by making use of spray drying and solvent evaporation methods (Alhalaweh A, et al. Preparation of zolmitriptan-chitosan microparticles by spray-drying for nasal delivery. 2010 Eur J Pharm Sci. 209; 38; 206-214). However, again the obtained co-crystals are far from nano-meter range having a size over 5 μm as evident from FIG. 1 of Alhalaweh et al., 2010. So no teaching with regard to the use of co-crystal formers for optimizing a nanonization procedure are disclosed therein.
WO2010080754 provides a pharmaceutical composition comprising nanoparticles comprising at least one aqueous-insoluble compound and at least one bile acid compound, wherein the aqueous-insoluble compound represents at least 76% of the total weight of aqueous-insoluble compound and bile acid compound in said nanoparticles. The exemplified formulations were all prepared by the solvent/anti-solvent process (bottom-up method) for nanonization. In this process the aqueous-insoluble compound(s) was first dissolved in an organic solvent, in particular ethanol, and subsequently mixed with an aqueous solution comprising the bile acid. However, in view of its use in the preparation of a medicament, one would like to reduce the use of organic solvents to a minimum. In preparing the formulations of the present invention, via milling (top-down method), no organic solvents need to be used, only aqueous suspensions are applied. Another disadvantage of the compositions described in WO2010080754 is the manufacturing price, as it is generally known that bile acid compounds are about 10-50× more expensive compared to dicarboxylic acids. Furthermore, cocrystal formation of drugs making use of dicarboxylic acids according to the present invention results in drugs comprising cocrystals having a particle size in the nanometer range as well as an improved stability in suspension.